Fused heterocyclic isoxazoline derivatives and their use as anti-depressants

ABSTRACT

The invention concerns fused heterocyclic isoxazoline derivatives of Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof and the N-oxide form thereof, more in particular, tetrahydropyranoisoxazole, hexahydroisoxazolopyridine, tetrahydrothiopyrano isoxazole and hexahydrobenzoisoxazole derivatives fused to a heterocyclic ring system via the 6-membered ring of the bicyclic moiety as well as processes for their preparation, pharmaceutical compositions comprising them and their use as a medicine, in particular for treating depression, anxiety, movement disorders, psychosis, Parkinson&#39;s disease and body weight disorders including anorexia nervosa and bulimia, wherein the variables are defined as in Claim  1.  The compounds have surprisingly been shown to have selective serotonine (5-HT) reuptake inhibitor activity as well as α 2 -adrenoceptor antagonist activity, compounds according to the invention are also suitable for treatment and/or prophylaxis in diseases where either one of the activities alone or the combination of said activities may be of therapeutic use.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the national stage of Application No.PCT/EP03/50377, filed Aug. 13, 2003, which application claims priorityfrom EP Patent Application No. 02078373.4 filed Aug. 15, 2002.

The invention concerns fused heterocyclic isoxazoline derivatives, morein particular tetrahydropyranoisoxazole, hexahydroisoxazolopyridine,tetrahydrothiopyrano-isoxazole and hexahydrobenzoisoxazole derivativesfused to a heterocyclic ring system via the 6-membered ring of thebicyclic moiety as well as processes for their preparation,pharmaceutical compositions comprising them and their use as a medicine,in particular for treating depression, anxiety, movement disorders,psychosis, Parkinson's disease and body weight disorders includinganorexia nervosa and bulimia.

The invention also relates to novel combination of said fusedheterocyclic isoxazoline derivatives with antidepressants, anxiolytics,antipsychotics and anti-Parkinson's disease drugs.

Tetrahydronaphtalene and indane derivatives showing anti-depressantactivity are known from EP-361 577 B1. These compounds are typicalmonoamine reuptake blockers with additional α₂-adrenoceptor antagonistactivity and they show anti-depressant activity without being sedative.

The problems associated with the compounds according to the state of theart is that the compounds cause considerable side-effects, such asnausea, excitation, an increased heart rate and a reduced sexualfunction. Furthermore, it requires a long time, in particular 3-4 weeks,before the response starts.

The purpose of the present invention is to provide novel compounds fortreating depression, anxiety, movement disorders, psychosis,schizophrenia and body weight disorders, in particular compounds that donot exhibit the aforementioned disadvantages.

The present invention relates to novel isoxazoline derivatives accordingto the general Formula (I)

the pharmaceutically acceptable acid or base addition salts thereof, thestereochemically isomeric forms thereof and the N-oxide form thereof,wherein:

-   X is CH₂, N—R⁷, S or O;-   R⁷ is selected from the group of hydrogen, alkyl, Ar, Ar-alkyl,    alkylcarbonyl, alkyloxycarbonyl and mono- and dialkylaminocarbonyl;-   B is a radical, optionally substituted with r radicals R¹, according    to anyone of Formula (B-a) or (B-b) and fused to the isoxazolinyl    moiety by either of the bond pairs (c,d), (d,e) or (e,f)

-   -   wherein    -   Het is an optionally substituted 5- or 6-membered heterocyclic        ring, selected from the group of pyridinyl, pyrazinyl,        pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, oxazolyl,        thiazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl,        oxadiazolyl and triazolyl;

-   each R¹ is, independently from each other, selected from the group    of hydrogen, hydroxy, amino, nitro, cyano, halo and alkyl and, only    when R¹ is attached to a N-atom, is further selected from the group    of alkyloxyalkyl, alkyloxyalkyloxyaLkyl, alkyloxycarbonylalkyl,    formyl, alkylcarbonyl, alkyloxycarbonyl, alkyloxyalkylcarbonyl and    mono- and dialkylamino-carbonyl;

-   r is an integer ranging from 0 to 6;

-   a and b are asymmetric centers;

-   (CH₂)_(m) is a straight hydrocarbon chain of m carbon atoms, m being    an integer ranging from 1 to 4;

-   Pir is a radical according to any one of Formula (IIa), (IIb) or    (IIc)

-   -   optionally substituted with n radicals R⁸, wherein:    -   each R⁸ is independently from each other, selected from the        group of hydroxy, amino, nitro, cyano, halo and alkyl;    -   n is an integer ranging from 0 to 5;    -   R⁹ is selected from the group of hydrogen, alkyl and formyl;

-   R³ represents an optionally substituted aromatic homocyclic or    heterocyclic ring system together with an optionally substituted and    partially or completely hydrogenated hydrocarbon chain of 1 to 6    atoms long with which said ring system is attached to the Pir    radical and of which may contain one or more heteroatoms selected    from the group of O, N and S; and

-   Ar is phenyl or naphthyl, optionally substituted with one or more    halo, cyano, oxo, hydroxy, alkyl, formyl, alkyloxy or amino    radicals.

More in particular, the invention relates to compounds according toFormula (I), the pharmaceutically acceptable acid or base addition saltsthereof, the stereochemically isomeric forms thereof and the N-oxideform thereof, wherein R³ is a radical according to any one of Formula(IIIa), (IIIb) or (IIIc)

wherein:

-   d is a single bond while Z is a bivalent radical selected from the    group of —CH₂—, —C(═O)—, —CH(OH)—, —C(═N—OH)—, —CH(alkyl)—, —O—,    —S—, —S(═O)—, —NH— and —SH—; or d is a double bond while Z is a    trivalent radical of formula ═CH— or ═C(alkyl)-;-   A is a 5- or 6-membered aromatic homocyclic or heterocyclic ring,    selected from the group of phenyl, pyranyl, pyridinyl, pyrazinyl,    pyrimidinyl, pyridazinyl, thienyl, isothiazolyl, pyrrolyl,    imidazolyl, pyrazolyl, furanyl, oxadiazolyl and isoxazolyl;-   p is an integer ranging from 0 to 6;-   R⁴ and R⁵ are each, independently from each other, selected from the    group of hydrogen, alkyl, Ar, biphenyl, halo and cyano ; or-   R⁴ and R⁵ may be taken together to form a bivalent radical    —R⁴—R⁵-selected from the group of —CH₂—, ═CH—, —CH₂—CH₂—, —CH═CH—,    —O—, —NH—, ═N—, —S, —CH₂N(-alkyl)- , —N(-alkyl)CH₂—, —CH₂NH—,    —NHCH₂—, —CH═N—, —N═CH, —CH₂O— and —OCH₂—;-   each R⁶ is independently from each other, selected from the group of    hydroxy, amino, nitro, cyano, halo, carboxyl, alkyl, Ar, alkyloxy,    Ar-oxy, alkyl-carbonyloxy, alkyloxycarbonyl, alkylthio, mono- and    di(alkyl)amino, alkylcarbonylamino, mono- and    di(aLkyl)aminocarbonyl, mono- and di(alkyl)aminocarbonyloxy, mono-    and di(alkyl)aminoalkyloxy ; or-   two vicinal radicals R⁶ may be taken together to form a bivalent    radical —R⁶—R⁶ —selected from the group of —CH₂—CH₂—O—, —O—CH₂—CH₂—,    —O—CH₂—C(═O)—, —C(═O)—CH₂—O—, —O—CH₂—O—, —CH₂—O—CH₂—, —O—CH₂—CH₂—O—,    —CH═CH—CH═CH—, —CH═CH—CH═N—, —CH═CH—N═CH—, —CH═N—CH═CH—,    —N═CH—CH═CH—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—C(═O)—, —C(═O)—CH₂—CH₂—,    —CH₂—C(═O)—CH₂— and —CH₂—CH₂—CH₂—CH₂— and-   R¹⁶ is selected from the group of hydrogen, alkyl, Ar and Ar-alkyl.

Preferably, the invention relates to those compounds according toFormula (I), the pharmaceutically acceptable acid or base addition saltsthereof, the stereochemically isomeric forms thereof and the N-oxideform thereof, wherein X=O; m=1; B is a radical according to Formula(B-a) or (B-b), Pir is a radical according to Formula (IIa) wherein n=0;R³ is a radical according to according to any one of Formula (IIIa),(IIIb) or (IIIc) wherein d is a double bond while Z is a trivalentradical of formula ═CH— or ═C(alkyl)—; A is a phenyl ring ; R⁴ishydrogen or alkyl ; R⁵ and R¹⁶ are each hydrogen ; R⁶ is hydrogen orhalo and p=1.

Preferably, the invention relates to those compounds according toFormula (I), the pharmaceutically acceptable acid or base addition saltsthereof, the stereochemically isomeric forms thereof and the N-oxideform thereof, wherein Het is selected from the group of pyridinyl,thienyl and pyrrolyl, each radical optionally substituted on a N atomwith a radical selected from the group of hydrogen, alkyl,alkyloxyallcyloxyalkyl, alkyloxycarbonylalkyl, alkylcarbonyl,alkyloxycarbonyl and alkyloxyalkylcarbonyl.

In the framework of this application, alkyl defines straight or branchedsaturated hydrocarbon radicals having from 1 to 6 carbon atoms, forexample methyl, ethyl, propyl, butyl, 1-methylpropyl, 1,1-dimethylethyl,pentyl, hexyl ; or alkyl defines cyclic saturated hydrocarbon radicalshaving from 3 to 6 carbon atoms, for example cyclopropyl,methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Thedefinition of alkyl also comprises alkyl radicals that are substitutedwith one or more halo, cyano, oxo, hydroxy, formyl or amino radicals,for example hydroxyalkyl, in particular hydroxymethyl and hydroxyethyland polyhaloalkyl, in particular difluoromethyl and trifluoromethyl.

In the framework of this application, Ar is phenyl or naphthyl,optionally substituted with one or more halo, cyano, oxo, hydroxy,alkyl, formyl, alkyloxy or amino radicals, such as for example,3-fluoro-phenyl of 3-fluoro-naphthyl.

In the framework of this application, halo is generic to fluoro, chloro,bromo and iodo.

The pharmaceutically acceptable salts are defined to comprise thetherapeutically active non-toxic acid addition salts forms that thecompounds according to Formula (I) are able to form. Said salts can beobtained by treating the base form of the compounds according to Formula(I) with appropriate acids, for example inorganic acids, for examplehydrohalic acid, in particular hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid and phosphoric acid ; organic acids, forexample acetic acid, hydroxyacetic acid, propanoic acid, lactic acid,pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid,fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,cyclamic acid, salicyclic acid, p-aminosalicylic acid and pamoic acid.

The compounds according to Formula (I) containing acidic protons mayalso be converted into their therapeutically active non-toxic metal oramine addition salts forms by treatment with appropriate organic andinorganic bases. Appropriate base salts forms comprise, for example, theammonium salts, the alkaline and earth alkaline metal salts, inparticular lithium, sodium, potassium, magnesium and calcium salts,salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine,hybramine salts, and salts with amino acids, for example arginine andlysine.

Conversely, said salts forms can be converted into the free forms bytreatment with an appropriate base or acid.

The term addition salt as used in the framework of this application alsocomprises the solvates that the compounds according to Formula (I) aswell as the salts thereof, are able to form. Such solvates are, forexample, hydrates and alcoholates.

The N-oxide forms of the compounds according to Formula (I) are meant tocomprise those compounds of Formula (I) wherein one or several nitrogenatoms are oxidized to the so-called N-oxide, particularly those N-oxideswherein one or more nitrogens of the piperazinyl radical are N-oxidized.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible isomeric forms that the compounds of Formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. More inparticular, stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or trans-configuration. Compounds encompassing doublebonds can have an E or Z-stereochemistry at said double bond.Stereochemically isomeric forms of the compounds of Formula (I) areobviously intended to be embraced within the scope of this invention.

Following CAS nomenclature conventions, when two stereogenic centers ofknown absolute configuration are present in a molecule, an R or Sdescriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) tothe lowest-numbered chiral center, the reference center. Theconfiguration of the second stereogenic center is indicated usingrelative descriptors [R*,R*] or [R*,S*], where R* is always specified asthe reference center and [R*,R*] indicates centers with the samechirality and [R*,S*] indicates centers of unlike chirality. Forexample, if the lowest-numbered chiral center in the molecule has an Sconfiguration and the second center is R, the stereo descriptor would bespecified as S—[R*,S*]. If “α” and “β” are used: the position of thehighest priority substituent on the asymmetric carbon atom in the ringsystem having the lowest ring number, is arbitrarily always in the “α”position of the mean plane determined by the ring system. The positionof the highest priority substituent on the other asymmetric carbon atomin the ring system (hydrogen atom in compounds according to Formula (I))relative to the position of the highest priority substituent on thereference atom is denominated “α”, if it is on the same side of the meanplane determined by the ring system, or “β”, if it is on the other sideof the mean plane determined by the ring system.

Compounds according to Formula (I) and some of the intermediatecompounds have at least two stereogenic centers in their structure,respectively denoted a and b in Formula (I). Due to the syntheticpathway followed for the synthesis of the tricyclic system, theconfiguration of those two asymmetric centers a and b is predetermined,so that the relative configuration of center a is S* and of center b isR*.

The invention also comprises derivative compounds (usually called“pro-drugs”) of the pharmacologically-active compounds according to theinvention, which are degraded in vivo to yield the compounds accordingto the invention. Pro-drugs are usually (but not always) of lowerpotency at the target receptor than the compounds to which they aredegraded. Pro-drugs are particularly useful when the desired compoundhas chemical or physical properties that make its administrationdifficult or inefficient. For example, the desired compound may be onlypoorly soluble, it may be poorly transported across the mucosalepithelium, or it may have an undesirably short plasma half-life.Further discussion on pro-drugs may be found in Stella, V. J. et al.,“Prodrugs”, Drug Delivery Systems, 1985, pp. 112-176, and Drugs, 1985,29, pp. 455-473.

Pro-drugs forms of the pharmacologically-active compounds according tothe invention will generally be compounds according to Formula (I), thepharmaceutically acceptable acid or base addition salts thereof, thestereochemically isomeric forms thereof and the N-oxide form thereof,having an acid group which is esterified or amidated. Included in suchesterified acid groups are groups of the formula —COOR^(x), where R^(x)is a C₁₋₆alkyl, phenyl, benzyl or one of the following groups:

Amidated groups include groups of the formula —CONR^(y)R^(z), whereinR^(y) is H, C₁₋₆alkyl, phenyl or benzyl and R^(z) is —OH, H, C₁₋₆alkyl,phenyl or benzyl.

Compounds according to the invention having an amino group may bederivatised with a ketone or an aldehyde such, as formaldehyde to form aMannich base. This base will hydrolyze with first order kinetics inaqueous solution.

The compounds of Formula (I) as prepared in the processes describedbelow may be synthesized in the form of racemic mixtures of enantiomersthat can be separated from one another following art-known resolutionprocedures. The racemic compounds of Formula (I) may be converted intothe corresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of Formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound would be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The compounds according to the invention, in particular compoundsaccording to Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof andthe N-oxide form thereof, have surprisingly been shown to have selectiveserotonine (5-HT) reuptake inhibitor activity in combination withadditional α₂-adrenoceptor antagonist activity and show a stronganti-depressant and/or anxiolytic activity and/or antipsychotic and/or abody weight control activity without being sedative. Also, in view oftheir selective serotonine (5-HT) reuptake inhibitor as well asα₂-adrenoceptor antagonist activity, compounds according to theinvention are also suitable for treatment and/or prophylaxis in diseaseswhere either one of the activities alone or the combination of saidactivities may be of therapeutic use. In particular, the compoundsaccording to the invention may be suitable for treatment and/orprophylaxis in the following diseases:

-   Central nervous system disorders, including:    -   Mood disorders, including particularly major depressive        disorder, depression with or without psychotic features,        catatonic features, melancholic features, atypical features of        postpartum onset and, in the case of recurrent episodes, with or        without seasonal pattern, dysthymic disorder, bipolar I        disorder, bipolar II disorder, cyclothymic disorder, recurrent        brief depressive disorder, mixed affective disorder, bipolar        disorder not otherwise specified, mood disorder due to a general        medical condition, substance-induced mood disorder, mood        disorder not otherwise specified, seasonal affective disorder        and premenstrual dysphoric disorders.    -   Anxiety disorders, including panic attack, agoraphobia, panic        disorder without agoraphobia, agoraphobia without history of        panic disorder, specific phobia, social phobia,        obsessive-compulsive disorder, posttraumatic stress disorder,        acute stress disorder, generalized anxiety disorder, anxiety        disorder due to a general medical condition, substance-induced        anxiety disorder and anxiety disorder not otherwise specified.    -   Stress-related disorders associated with depression and/or        anxiety, including acute stress reaction, adjustment disorders        (brief depressive reaction, prolonged depressive reaction, mixed        anxiety and depressive reaction, adjustment disorder with        predominant disturbance of other emotions, adjustment disorder        with predominant disturbance of conduct, adjustment disorder        with mixed disturbance of emotions and conduct, adjustment        disorders with other specified predominant symptoms) and other        reactions to severe stress.    -   Dementia, amnesic disorders and cognitive disorders not        otherwise specified, especially dementia caused by degenerative        disorders, lesions, trauma, infections, vascular disorders,        toxins, anoxia, vitamin deficiency or endocrinic disorders, or        amnesic disorders caused by alcohol or other causes of thiamin        deficiency, bilateral temporal lobe damage due to Herpes simplex        encephalitis and other limbic encephalitis, neuronal loss        secondary to anoxia/hypoglycemia/severe convulsions and surgery,        degenerative disorders, vascular disorders or pathology around        ventricle III.    -   Cognitive disorders due to cognitive impairment resulting from        other medical conditions.    -   Personality disorders, including paranoid personality disorder,        schizoid personality disorder, schizotypical personality        disorder, antisocial personality disorder, borderline        personality disorder, histrionic personality disorder,        narcissistic personality disorder, avoidant personality        disorder, dependent personality disorder, obsessive-compulsive        personality disorder and personality disorder not otherwise        specified.    -   Schizoaffective disorders resulting from various causes,        including schizoaffective disorders of the manic type, of the        depressive type, of mixed type, paranoid, disorganized,        catatonic, undifferentiated and residual schizophrenia,        schizophreniform disorder, schizoaffective disorder, delusional        disorder, brief psychotic disorder, shared psychotic disorder,        substance-induced psychotic disorder and psychotic disorder not        otherwise specified.    -   Akinesia, akinetic-rigid syndromes, dyskinesia and        medication-induced parkinsonism, Gilles de la Tourette syndrome        and its symptoms, tremor, chorea, myoclonus, tics and dystonia.    -   Attention-deficit/hyperactivity disorder (ADHD).    -   Parkinson's disease, drug-induced Parkinsonism,        post-encephalitic Parkinsonism, progressive supranuclear palsy,        multiple system atrophy, corticobasal degeneration,        parkinsonism-ALS dementia complex and basal ganglia        calcification.    -   Dementia of the Alzheimer's type, with early or late onset, with        depressed mood.    -   Behavioral disturbances and conduct disorders in dementia and        the mentally retarded, including restlessness and agitation.    -   Extra-pyramidal movement disorders.    -   Down's syndrome.    -   Akathisia.    -   Eating Disorders, including anorexia nervosa, atypical anorexia        nervosa, bulimia nervosa, atypical bulimia nervosa, overeating        associated with other psychological disturbances, vomiting        associated with other psychological disturbances and        non-specified eating disorders.    -   AIDS-associated dementia.-   Chronic pain conditions, including neuropathic pain, inflammatory    pain, cancer pain and post-operative pain following surgery,    including dental surgery. These indications might also include acute    pain, skeletal muscle pain, low back pain, upper extremity pain,    fibromyalgia and myofascial pain syndromes, orofascial pain,    abdominal pain, phantom pain, tic douloureux and atypical face pain,    nerve root damage and arachnoiditis, geriatric pain, central pain    and inflammatory pain. Neurodegenerative diseases, including    Alzheimer's disease, Huntington's chorea, Creutzfeld-Jacob disease,    Pick's disease, demyelinating disorders, such as multiple sclerosis    and ALS, other neuropathies and neuralgia, multiple sclerosis,    amyotropical lateral sclerosis, stroke and head trauma.-   Addiction disorders, including:    -   Substance dependence or abuse with or without physiological        dependence, particularly where the substance is alcohol,        amphetamines, amphetamine-like substances, caffeine, cannabis,        cocaine, hallucinogens, inhalants, nicotine, opioids,        phencyclidine, phencyclidine-like compounds, sedative-hypnotics,        benzodiazepines and/or other substances, particularly useful for        treating withdrawal from the above substances and alcohol        withdrawal delirium.    -   Mood disorders induced particularly by alcohol, amphetamines,        caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine,        opioids, phencyclidine, sedatives, hypnotics, anxiolitics and        other substances.    -   Anxiety disorders induced particularly by alcohol, amphetamines,        caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine,        opioids, phencyclidine, sedatives, hypnotics, anxiolitics and        other substances and adjustment disorders with anxiety.-   Smoking cessation.-   Body weight control, including obesity.-   Sleep disorders and disturbances, including    -   Dyssomnias and/or parasomnias as primary sleep disorders, sleep        disorders related to another mental disorder, sleep disorder due        to a general medical condition and substance-induced sleep        disorder.    -   Circadian rhythms disorders.    -   Improving the quality of sleep.-   Sexual dysfunction, including sexual desire disorders, sexual    arousal disorders, orgasmic disorders, sexual pain disorders, sexual    dysfunction due to a general medical condition, substance-induced    sexual dysfunction and sexual dysfunction not otherwise specified.

The present invention thus also relates to compounds according toFormula (I), the pharmaceutically acceptable acid or base addition saltsthereof, the stereochemically isomeric forms thereof, the N-oxide formthereof, as well as the prodrugs thereof for use as a medicine, inparticular for the treatment and/or prophylaxis of depression, anxiety,movement disorders, psychosis, Parkinson's disease and body weightdisorders.

The present invention also relates to a method for the treatment and/orprophylaxis of diseases where either one of the activities (selectiveserotonine (5-HT) reuptake inhibitor and α₂-adrenoceptor antagonistactivity) alone or the combination of said activities may be oftherapeutic use, in particular for the treatment and/or prophylaxis ofdepression, anxiety, movement disorders, psychosis, Parkinson's diseaseand body weight disorders comprising administering to a human in need ofsuch administration an affective amount of a compound according to theinvention, in particular according to Formula (I), the pharmaceuticallyacceptable acid or base addition salts thereof, the stereochemicallyisomeric forms thereof, the N-oxide form thereof, as well as thepro-drugs thereof.

The invention also relates to a pharmaceutical composition comprising apharmaceutically acceptable carrier and, as active ingredient, atherapeutically effective amount of a compound according to theinvention, in particular a compound according to Formula (I), thepharmaceutically acceptable acid or base addition salts thereof, thestereochemically isomeric forms thereof and the N-oxide form thereof ora prodrug as defined above.

The compounds according to the invention, in particular the compoundsaccording to Formula (I), the pharmaceutically acceptable acid or baseaddition salts thereof, the stereochemically isomeric forms thereof andthe N-oxide form thereof and the prodrugs, or any subgroup thereof maybe formulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, in particular, for administration orally,rectally, percutaneously, by parenteral injection or by inhalation. Forexample, in preparing the compositions in oral dosage form, any of theusual pharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations that are intended tobe converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

The compounds according to the invention may also be suitable as add-ontreatment and/or prophylaxis in the above listed diseases in combinationwith any combination of compounds selected from the group ofantidepressants, anxiolytics, antipsychotics and/or anti-Parkinson'sdisease drugs which are currently available or in development or whichwill become available in the future, to improve efficacy and/or onset ofaction. This is evaluated in rodent models in which antidepressants,anxiolytics, antipsychotics and/or anti-Parkinson's disease drugs areshown to be active. For example, compounds are evaluated in combinationwith antidepressants, anxiolytics, antipsychotics and/oranti-Parkinson's disease drugs for attenuation of stress-inducedhyperthermia.

The invention therefore also relates to a pharmaceutical compositioncomprising the compounds according to the invention, in particular thecompounds according to Formula (I), the pharmaceutically acceptable acidor base addition salts thereof, the stereochemically isomeric formsthereof and the N-oxide form thereof, and the prodrugs and one or moreother compounds selected from the group of antidepressants, anxiolytics,antipsychotics and anti-Parkinson's disease drugs.

The invention also relates to the use of a pharmaceutical compositionaccording to the invention for the manufacture of a medicament toimprove efficacy and/or onset of action in the treatment and/orprophylaxis of depression, anxiety, movement disorders, psychosis,Parkinson's disease and body weight disorders.

Further, the invention relates to the use of a compound according to theinvention for the manufacture of a medicament for the treatment and/orprophylaxis of depression, anxiety, movement disorders, psychosis,Parkinson's disease and body weight disorders, said treatment comprisingthe simultaneous or sequential administration of a compound according tothe invention and one or more other compounds selected from the group ofantidepressants, anxiolytics, anti-psychosis and anti-Parkinson's drugs.The invention further relates to a process for making a pharmaceuticalcomposition comprising mixing a compound according to the invention, inparticular the compounds according to Formula (I), the pharmaceuticallyacceptable acid or base addition salts thereof, the stereochemicallyisomeric forms thereof and the N-oxide form thereof, and the prodrugs,or any subgroup thereof and a compound selected from the group ofantidepressants, anxiolytics, antipsychotics and anti-Parkinson'sdisease drugs and a pharmaceutically acceptable carrier.

In vitro receptor and neurotransmitter transporter binding andsignal-transduction studies can be used to evaluate the α₂-adrenoceptorantagonism activity and serotonine (5-HT reuptake inhibitor activity ofthe present compounds. As indices for central penetration and potency toblock the α₂-adrenoceptors and serotonin transporters, respectively, exvivo α₂-adrenoceptor and serotonin transporter occupancy can be used. Asindices of α₂-adrenoceptor antagonism in vivo, the reversal of the lossof righting reflex, observed in rats after subcutaneous injection ororal dosage of the compound before intravenous medetomidineadministration in rats can be used (medetomidine-test). As indices ofserotonine (5-HT) reuptake inhibition activity, the inhibition ofhead-twitches and excitation in rats, observed after subcutaneousinjection or oral dosage of the compound before subcutaneousp-chloroamphetamine administration in rats can be used (pCA-test).

The compounds according to the invention can generally be prepared by asuccession of steps, each of which is known to the skilled person.

In particular, the compounds according to Formula (I) with a Pir-radicalaccording to Formula (IIa), (IIb) or (IIc) can be prepared by anucleophilic substitution reaction with a substituted piperazineaccording to Formula (V) on an intermediate compound of Formula (IV).These reactions may be carried out in a reaction inert solvent such as1,4-dioxane, methylisobutylketone (MIBK), acetonitrile orN,N′-dimethylformamide, in the presence of a suitable base such asNaHCO₃, Na₂CO₃, piperidine or triethylamine, or even without a base,using in this latter case excess of reagent of Formula (V). Convenientreaction temperatures range between 100° C. and 150° C.

In compound (IV), L represents any suitable reactive leaving group, inparticular halo, such as chloro, bromo or iodo or sulfonyloxy, such as4-methylsulphonyloxy or 4-methylbenzenesulfonyloxy.

The compounds according to the invention can easily be converted intoeach other. In case the B-radical is an N-containing heterocyclicradical, such as e.g. indol, the nitrogen atom of such a final compoundaccording to Formula (I′) can be alkylated or acylated according toart-known procedures to give final compounds of Formula (I″). Alkylationreactions can be carried out in the presence of the correspondingalkylating agent, for example any haloalkyl compound, in the presence ofa base, such as NaOH, KOH, Na₂CO₃, K₂CO₃ or a mixture thereof, and aninert solvent, for example acetonitrile, tetrahydrofuran or a mixturethereof. Acylation reactions can be carried out in the presence of anacylating agent, for example acylhalides, isocyanates or acid anhydrides; a strong base, such as NaOH, KOH or BEMP(2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diaz-phosphorine)either or not supported in an inert polymer, such as polystyrene; and aninert solvent, for example dichloromethane or tetrahydrofuran. L is aleaving group, in particular halo such as chloro, bromo, iodo; orsulphonyloxy or 4-methylsulphonyloxy ; and R¹ is any alkyl or acylgroup.

The starting materials and some of the intermediate compounds arecompounds that are either commercially available or may be preparedaccording to conventional reaction procedures generally known in theart. For example, intermediate compounds of Formula (IV′) in which X=Omay be prepared according to the following reaction scheme 1.

An intermediate compound of Formula (IV′) can be prepared fromhydroxyaldehydes by reaction with commercially available crotonates inthe presence of a base, such as K₂CO₃, Na₂CO₃ or NaH in an inertsolvent, such as 2-propanone or dimethylformamide (step a). Theresulting intermediate compound is converted into the oxime in atemperature range of −10° C. to 0° C. using art-known techniques, suchas hydroxylamine hydrochloride in the presence of a suitable base, suchas AcONa, NaHCO₃ or pyridine in a reaction inert solvent, for exampleethanol (step b). The resulting oxime-intermediate compound is furtheroxidized into its nitrile oxide and the subsequent in situintramolecular cycloaddition yields an isoxazoline compound (step c).The oxidation can be carried out using sodium hypochlorite solution inthe presence of triethylamine in an inert solvent, such dichloromethaneat room temperature. Oxidation can also be performed using chloramine-Thydrate (N-chloro4-methylbenzene-sulphonamide, sodium salt), by stirringand heating in a solvent such as refluxing ethanol. At this stage twosteroisomers are formed. Reduction of the carbonyl radical in thepresence of a suitable reducting agent, for example sodium borohydride,in a suitable solvent, such as water, alcohol, tetrahydrofuran or amixture thereof, generally at room temperature yields thehydroxy-intermediate compound (step d), which is further converted intointermediate compound (IV′) using standard techniques (step e). Forexample, reaction with methanesulfonylchloride or4-methylbenzenesulfonyl-chloride in the presence of a base, such astriethylamine, in a reaction inert solvent, for example dichloromethane,at reaction temperatures ranging between 0° C. and room temperatureyields the corresponding sulfonyloxy derivative intermediate compound(IV′). The corresponding halo-derivative can also be prepared, e.g. bytreating the hydroxy-intermediate compound with triphenylphosphine, inthe presence of tetrachloromethane, in a reaction inert solvent, such astetrahydrofuran, and by stirring and refluxing the mixture. In somecases a protecting group (for example a tert-butoxycarbonyl group) maybe removed in step (d).

Specifically, indol-fused isoxazolidine derivatives may also be preparedas in the following reaction scheme 2

in which the hydroxyaldehyde intermediate compound is prepared asdescribe by Katsunori Teranishi et al. in Synthesis, 1994, (10),1018-1020 by hydrolysis of the ester in the presence of a strong base,such as LiOH or NaOH, water and an inert solvent, for example1,4-dioxane or tetrahydrofuran. The resulting hydroxy intermediatecompound is formylated using art-known procedures to yield thehydroxyaldehyde intermediate compound, such as a reaction withparaformaldehyde in the presence of an appropriate salt, for exampleMgCl₂, a base, for example triethylamine or diisopropylethylamine, andin an inert solvent, for example acetonitrile or tetrahydrofuran.

Specifically, pyrazine-fused isoxazolidine derivatives may be preparedaccording to the following reaction scheme 3.

Specifically, pyridazine-fused isoxazolidine derivatives may be preparedaccording to either one of the following schemes 4 and 5.

Specifically, pyrimidine-fused isoxazolidine derivatives may be preparedaccording to either one of the following schemes 6 and 7.

Specifically, benzofuran-fused isoxazolidine derivatives may be preparedaccording to the following scheme 8.

Specifically, benzoxazole-fused isoxazolidine derivatives may beprepared according to the following scheme 9.

The following examples illustrate the present invention without beinglimited thereto.Experimental Part

The carbon ring numbering system for the compounds according to Formula(I-B-b) used in this application is as follows:

Of some compounds the absolute stereochemical configuration of thestereogenic carbon atom(s) therein was not experimentally determined. Inthose cases the stereochemically isomeric form which was first isolatedis designated as “A” and the second as “B”, without further reference tothe actual stereochemical configuration. However, said “A” and “B”isomeric forms can be unambiguously characterized by a person skilled inthe art, using art-known methods such as, for example, X-raydiffraction. The stereogenic centers a and b in Formula (I) haverespectively the ring numbers 3a and 3.

Hereinafter, “DMF” is defined as N,N-dimethylformamide, “DIPE” isdefined as diisopropyl ether, “ACN” is defined as acetonitrile, “DCM” isdefined as dichloromethane and “THF” is defined as tetrahydrofurane.

A. Preparation of the Intermediate Compounds

Example A.1

Preparation of Intermediate Compound 7

a) To a solution of 57.1 g (0.176 mol) of chloro-acetic acid1-(2,2-dimethyl-propionyl)-1H-indol-6-yl ester in 500 ml of 1,4-dioxane,a solution of 5.05 g (0.211 mol) of LiOH in 100 ml of water was addedportionwise at room temperature. The reaction was stirred for 1 h atroom temperature. Then DCM and a 2N solution of HCl in water were added.The organic layer was separated, dried (Na₂SO₄), filtered off and thesolvent evaporated. The residue was purified by short open columnchromatography over silica gel (eluents: DCM and DCM/Ethyl acetate95/5). The desired fractions were collected and the solvent evaporated.Yielding: 28.3 g (74%) of1-(6-Hydroxy-indol-1-yl)-2,2-dimethyl-propan-1-one (intermediatecompound 1).

b) To a mixture of intermediate compound 1 (24.13 g, 0.111 mol),magnesium chloride (15.9 g, 0.167 mol) and diisopropylethylamine (72.5ml, 0.416 mol) in 600 ml of acetonitrile, 13.4 g (0.443 mol) ofparaformaldehyde were added. The reaction was heated to reflux for 60min, then additional 13.3 g (0.443 mol) of paraformadehyde were added.The reaction was heated to reflux for 60 min and 13.3 g (0.443 mol) ofparaformaldehyde were added again. The reaction was heated to reflux for2 h. The reaction was allowed to reach room temperature. Then a 1Nsolution of HCl in water and DCM were added. The organic layer wasseparated, dried (Na₂SO₄), filtered off and the solvent evaporated. Theresidue was purified by short open column chromatography over silica gel(eluent: DCM). The desired fractions were collected and the solventevaporated. Yielding: 12.83 g (47%) of1-(2,2-Dimethyl-propionyl)-6-hydroxy-1H-indole-5-carbaldehyde(intermediate compound 2).

c) 4-bromo-2-butenoic acid ethyl ester 14.2 ml (0.082 mol) was addedportionwise to a mixture of intermediate compound 2 (13.6 g, 0.055 mol)and K₂CO₃ (13.68 g, 0.099 mol) in DMF (60 ml). The reaction mixture wasstirred for 6 hours at room temperature, filtered and the filtrate wasevaporated to dryness. The residue was washed with water, then extractedwith DCM. The separated organic layer was dried (Na₂SO₄), filtered, andthe solvent was evaporated. The residue was purified by short opencolumn chromatography over silica gel (eluent: DCM and DCM/Ethyl acetate9/1). The desired fractions were collected and the solvent evaporated.Yielding: 21.05 g (100%, crude yield) of4-[1-(2,2-Dimethyl-propionyl)-5-formyl-1H-indol-6-yloxy]-but-2-enoicacid ethyl ester (intermediate compound 3).

d) Hydroxylamine hydrochloride (4.59 g, 0.066 mol) was added to amixture of intermediate compound 3 (21.05 g, 0.055 mol) and sodiumacetate (6.8 g, 0.066 mol) in ethanol (250 ml). The reaction mixture wasstirred for 1 h at 0° C., then water was added and extracted with DCM.The separated organic layer was dried (Na₂SO₄), filtered, and thesolvent was evaporated. Yielding: 21.0 g (100%, crude yield) of4-[1-(2,2-Dimethyl-propionyl)-5-(hydroxyimino-methyl)-1H-indol-6-yloxy]-but-2-enoicacid ethyl ester (intermediate compound 4).

e) NaClO, 4% (176.4 ml, 0.140 mol) was added portionwise at 0° C. to asolution of intermediate compound 4(19.4 g, 0.052 mol) in DCM (200 ml).The reaction was stirred for 1 h at room temperature. Then Et₃N (10.9ml, 0.078 mol) was added dropwise at 0° C. The reaction mixture wasstirred for 3 hours at room temperature, then organic layer wasseparated, dried (Na₂SO₄), filtered, and the filtrate was evaporated.The residue was purified by short open column chromatography over silicagel (eluent: DCM and DCM/Ethyl acetate 95/5). The desired fractions werecollected and the solvent was evaporated. The residue was washed withdiisopropyl ether and collected. Yielding: 4.25 g (22%) of7-(2,2-Dimethyl-propionyl)-3a,4-dihydro-3H,7H-2,5-dioxa-1,7-diaza-dicyclopenta[a,g]naphthalene-2-carboxylicacid ethyl ester (intermediate compound 5).

f) NaBH₄ (1.23 g, 0.0325 mol) was added portionwise to a solution ofintermediate compoundn 5 (4.25 g, 0.013 mol) in THF (100 ml) and H₂O (10ml), stirred and cooled on an ice-bath. The resulting reaction mixturewas stirred for 4 hours at room temperature. The reaction mixture wastreated with a 10% aqueous solution of ammonium chloride and extractedwith DCM. The separated organic layer was dried (Na₂SO₄), filtered andthe solvent evaporated. Yielding: 3.03 g of(3a,4-dihydro-3H,7H-2,5-dioxa-1,7-diaza-dicyclopenta[a,g]naphthalen-3-methanol(intermediate compound 6).

g) Et₃N (1.4 ml, 0.0101 mol) was added to a solution of intermediatecompound 6 (1.65 g, 0.00675 mol) in DMF (15 ml). The mixture was cooledin an ice-bath. Methanesulfonyl chloride (0.58 ml, 0.0075 mol) was addedand the resulting reaction mixture was stirred for 1 h at roomtemperature. Then, a saturated aqueous solution of NaHCO₃ was added andthe mixture was extracted with DCM, dried (Na₂SO₄), filtered and thesolvent was evaporated. The residue was washed with diisopropyl etherand the solid was collected. Yielding: 1.99 g (91%) of methanesulfonicacid3a,4-dihydro-3H,7H-2,5-dioxa-1,7-diaza-dicyclopenta[a,g]naphthalen-3-ylmethylester (intermediate compound 7).

Example A.2

Preparation of Intermediate Compound 15

a) To a mixture of NaH (22.5 g, 0.6 mol) in 50 ml of THF a solution of3-hydroxypyridine in 500 ml of THF was added dropwise at 0° C. undernitrogen atmosphere. The reaction was stirred for 15 min at 0° C., the asolution of methoxymethylchloride (45 ml, 0.55 mol) in 200 ml of THF wasadded portionwise at 0° C. The reaction was stirred at room temperatureovernight, then quenched with a 10% aqueous solution of ammoniumchloride and extracted with ethyl acetate, dried (Na₂SO₄), filtered andthe solvent was evaporated. The residue was purified by short opencolumn chromatography over silica gel (eluent: Heptane/Ethyl acetate 3/1and 2/1). The desired fraction was collected and the solvent evaporated.Yielding: 38.15 g (55%) of 3-methoxymethoxy-pyridine (intermediatecompound 8).

b) To a solution of intermediate compound 8 (19 g, 0.14 mol) andtetramethylethylene-diamine (23.2 ml, 0.15 mol) in 500 ml of ethylether, 60 ml of a solution 2.5M of butyllithium in THF was addeddropwise at −78° C. under nitrogen atmosphere. The reaction was stirredfor 2 h at −78° C., then methyl formate (10.9 ml, 0.18 mol) was addeddropwise at −78° C. The mixture was allowed to reach room temperatureand was stirred at this temperature overnight. Then a 10% aqueoussolution of citric acid was added and the organic layer was separated,dried (Na₂SO₄), filtered and the solvent was evaporated. The residue waspurified by short open column chromatography over silica gel (eluent:Heptane/Ethyl acetate 2/1). The desired fractions were collected and thesolvent evaporated. Yielding: 18.5 g (80%) of3-methoxymethoxypyridine-4-carboxaldehyde (intermediate compound 9).

c) Hydroxylamine hydrochloride (17.22 gg, 0.248 mol) was added at 0° C.to a mixture of intermediate compound 9 (34.08 g, 0.208 mol) and sodiumacetate (25.59 g, 0.312 mol) in ethanol (250 ml). The reaction mixturewas stirred overnight at room temperature, then water was added andextracted with DCM. The separated organic layer was dried (Na₂SO₄),filtered, and the solvent was evaporated. The residue was washed withdiisopropylether with few drops of DCM and the solid was collected.Yielding: 26.24 g (69%) of 3-methoxymethoxy-pyridine-4-carbaldehydeoxime (intermediate compound 10).

d) To a mixture of intermediate compound 10 (26.24 g, 0.143 mol) in 400ml of DCM, NaClO (4%) (485 ml, 0.286 mol) was added dropwise at 0° C.The reaction was stirred for 1 h at 0° C. and 2 h at room temperature.Then dimethyl fumarate (31.0 g, 0.215 mol) was added at 0° C. andtriethylamine (29.6 ml, 0.215 mol) was added dropwise at 0° C. Thereaction was stirred overnight at room temperature. The organic layerwas separated, dried (Na₂SO₄), filtered and the solvent was evaporated.The residue was purified by short open column chromatography over silicagel (eluent: Heptane/Ethyl acetate 1/1, 1/3 and pure ethyl acetate). Thedesired fractions were collected and the solvent evaporated. Yielding:13.45 g (29%) of3-(3-methoxymethoxy-pyridin-4-yl)-4,5-dihydro-isoxazole-4,5-dicarboxylicacid dimethyl ester (intermediate compound 11).

e) To a solution of 13.45 g (0.041 mol) of intermediate compound 11,52.1 ml of a solution 1M of lithiumaluminium hydride was added dropwiseat 0° C. under nitrogen atmosphere. The reaction was stirred for 2 h at0° C. The excess of hydride was quenched with a saturated aqueoussolution of ammonium chloride. The solid was filtered off through aCELITE pad and the filtrate was extracted with ethyl acetate. Theorganic layer was separated, dried (Na₂SO₄), filtered and the solventwas evaporated. The residue was purified by short open columnchromatography over silica gel (eluent: Ethyl acetate, Ethylacetate/MeOH saturated with ammonia 97.5/2.5, 95/5 and 9/1). The desiredfractions were collected and the solvent evaporated. Yielding: 3.8 g(34%) of[4-hydroxymethyl-3-(3-methoxymethoxy-pyridin-4-yl)-4,5-dihydro-isoxazol-5-yl]-methanol(intermediate compound 12).

f) To a solution of intermediate compound 12 (3.8 g, 0.0142 mol) in 100ml of DCM, 25 ml of triflouroacetic acid were added portionwise at roomtemperature. The reaction was stirred overnight at room temperature. Thesolvent was evaporated and the residue was co-evaporated with ethanol.Yielding 4.79 g (100, crude product) of4-(4,5-bis-hydroxymethyl-4,5-dihydro-isoxazol-3-yl)-pyridin-3-ol(intermediate compound 13).

g) To a solution of intermediate compound 13 (4.8 g, 0.0142 mol) in 50ml of THF, triethylamine (19.9 ml, 0.0142 mol) at room temperature. Themixture was stirred at room temperature for 15 min, then triphenylphosphine polymer bounded (loading 1.6 mmol/g) was added (17.75 g,0.0284 mol) at room temperature and diethylazadicarboxylate (27.8 ml,0.0178 mol) was added dropwise at room temperature. The reaction washeated to reflux for 2 h. The solid was filtered off through a CELITEpad and the filtrate was evaporated. The residue was dissolved in DCMand treated with water. The organic layer was separated, dried (Na₂SO₄),filtered and the solvent was evaporated. The residue was washed withacetonitrile/diisopropyl ether and the solid was collected. Yielding3.07 g (100%, crude product) of(3a,4-dihydro-3H-2,5-dioxa-1,7-diaza-cyclopenta[a]naphthalen-3-yl)-methanol(intermediate compound 14).

h) Intermediate compound 14 (1.72 g, 0.0083 mol) was treated under thereaction conditions described in Example A.1 g using DCM as solvent.Yielding: 0.66 g of methanesulfonic acid3a,4-dihydro-3H-2,5-dioxa-1,7-diaza-cyclopenta[a]naphthalen-3-ylmethylester (intermediate compound 15).

Example A.3

Preparation of Intermediate Compound 16

To a solution of intermediate compound 14 (1 g, 0.0048 mol) and CBr₄(2.41 g, 0.0073 mol) in 100 ml of DCM, triphenyl phosphine polymerbounded (loading 1.6 mmol/g) was added (4.56 g, 0.0073 mol). Thereaction was stirred overnight at room temperature, then the solid wasfiltered off through a CELITE pad and the filtrate was evaporated. Theresidue was purified by short open column chromatography over silica gel(eluent: DCM/Ethyl acetate 1/1). The desired fractions were collectedand the solvent evaporated. Yielding: 0.62 g (48%) of3-bromomethyl-3a,4-dihydro-3H-2,5-dioxa-1,7-diaza-cyclopenta[a]naphthalene(intermediate compound 16).

Example A.4

Preparation of Intermediate Compound 29

a) 2-Bromopyridine-3-carboxaldehyde (9.6 g, 0.052 mol) was treated underthe reaction conditions described in Example A.2c. Yielding: 5.91 g(56%) of 2-Bromo-pyridine-3-carbaldehyde oxime (intermediate compound17).

b) To a solution of intermediate compound 17 (5.91 g, 0.0294 mol) andpyridine (catalytic amount) in 100 ml of CHCl₃, N-chlorosuccinimide(4.32 g, 0.032 mol) was added portionwise at room temperature. Thereaction was heated to reflux temperature for 30 min. After cooling to0° C., dimethyl fumarate (4.24 g, 0.0294 mol) and triethylamine (4.91ml, 0.035 mol) were added. The reaction was stirred for 48 h at roomtemperature. Then a saturated aqueous solution of NaCO₃ was added andthe organic layer was separated, dried (Na₂SO₄), filtered and thesolvent was evaporated. The residue was purified by short open columnchromatography over silica gel (eluent: DCM/Ethyl acetate 95/5). Thedesired fractions were collected and the solvent evaporated. Yielding:9.14 g (90%) of3-(2-bromo-pyridin-3-yl)-4,5-dihydro-isoxazole-4,5-dicarboxylic aciddimethyl ester (intermediate compound 18).

c) To a solution of intermediate compound 18 (9.14 g, 0.027 mol) in 130ml of tetrahydrofuran and 16 ml of ethanol, sodium borohydride (2.51 g,0.066 mol) was added portionwise at 0° C. The reaction was stirred atthis temperature for 90 min. Then a saturated solution of ammoniumchloride was added. The mixture was extracted with ethyl acetate andn-BuOH. The combined organic solutions were dried (Na₂SO₄), filtered andthe solvent was evaporated. The residue was purified by short opencolumn chromatography over silica gel (eluent: Ethyl acetate, Ethylacetate/MeOH saturated with ammonia 85/15). The desired fractions werecollected and the solvent evaporated. Yielding: 6.8 g, (88%) of[3-(2-bromo-pyridin-3-yl)-5-hydroxymethyl-4,5-dihydro-isoxazol4-yl]-methanol(intermediate compound 19).

d) A mixture of intermediate compound 19 (6.8 g, 0.0236 mol), K₂CO₃ (7.2g, 0.052 mol) and 18-crown-6 (1,4,7,10,13,16-hexaoxa-cyclooctadecane)(catalytic amount) in methylisobutyl ketone was heated to refluxovernight. Then water was added and the organic layer was separated,dried (Na₂SO₄), filtered and the solvent was evaporated. The residue waspurified by short open column chromatography over silica gel (eluent:Ethyl acetate, Ethyl acetate/MeOH saturated with ammonia 97.5/2.5, 95/5and 9/1). The desired fractions were collected and the solventevaporated. Yielding: 0.48 g (10%) of(3a,4-dihydro-3H-2,5-dioxa-1,6-diaza-cyclopenta[a]naphthalen-3-yl)-methanol(intermediate compound 20).

e) Intermediate compound 20 (0.46 g, 0.00223 mol) was treated under thereaction conditions described in Example A.3. Yielding: 0.120 g (37%) of3-bromomethyl-3a,4-dihydro-3H-2,5-dioxa-1,6-diaza-cyclopenta[a]naphthalene(intermediate compound 21).

Example A.5

Preparation of Intermediate Compound 29

a) To a solution of 2-hydroxymethyl-3-hydroxypyridine hydrochloride (10g, 0.062 mol) in 100 ml of DMF, imidazole (8.44 g, 0.124 mol) was addedat room temperature. The solution was stirred for 30min at roomtemperature. Then tert-buthyldiphenylsilyl chloride (32 ml, 0.124 mol)was added dropwise at room temperature. The reaction was stirredovernight at room temperature, then the solvent was evaporated, theresidue was taken up in DCM and washed with water. The organic layer wasseparated, dried (Na₂SO₄), filtered and the solvent was evaporated. Theresidue was purified by short open column chromatography over silica gel(eluent: Heptane/Ethyl acetate 1/1). The desired fractions werecollected and the solvent evaporated. Yielding: 12.3 g (54%) of2-(tert-butyl-diphenyl-silanyloxymethyl)-pyridin-3-ol (intermediatecompound 22).

b) To a mixture of intermediate compound 22 (12.3 g, 0.034 mol) andK₂CO₃ (9.4 g, 0.068 mol) in DMF, 4-bromo-2-butenoic acid ethyl ester(9.36 ml, 0.068 mol) was added dropwise at 0° C., then the reaction wasstirred overnight at room temperature. The solvent was evaporated, theresidue was taken up in DCM and washed with water. The organic layer wasseparated, dried (Na₂SO₄), filtered and the solvent was evaporated. Theresidue was purified by short open column chromatography over silica gel(eluent: Heptane/Ethyl acetate 1/1). The desired fractions werecollected and the solvent evaporated. Yielding: 8.72 g (54%) of4-[2-(tert-butyl-diphenyl-silanyloxymethyl)-pyridin-3-yloxy]-but-2-enoicacid ethyl ester (intermediate compound 23).

c) To a solution of pyridine (5 ml) in 6 ml of tetrahydrofuran,pyridinium fluoride (2.5 ml) was added dropwise at 0° C. under nitrogenatmosphere and the mixture was stirred at that temperature for 15 min.Then a solution of intermediate compound 23 (8.72 g, 0.018 mol) in 16 mlof tetahydrofurane was added at 0° C. The reaction was stirred at thattemperature for 2 h, then neutralized by addition of a saturated aqueoussolution of NaHCO₃ (pH=6). The resulting mixture was extracted with DCM,the organic layer was separated, dried (Na₂SO₄), filtered and thesolvent was evaporated. Yielding: 7.54 g (100%, crude product) of4-(2-hydroxymethyl-pyridin-3-yloxy)-but-2-enoic acid ethyl ester(intermediate compound 24).

d) To a solution of intermediate compound 24 (7.5 g, 0.032 mol) in 150ml of DCM, MnO₂ (27.8 g, 0.32 mol) was added at room temperature. Thereaction was stirred overnight at room temperature, then the solid wasfiltered off through CELITE pad. The filtrate solvent was evaporated andthe residue was purified by short open column chromatography over silicagel (eluent: Heptane/Ethyl acetate 1/1 and 1/4). The desired fractionswere collected and the solvent evaporated. Yielding: 1.066 g (39%) of4-(2-formyl-pyridin-3-yloxy)-but-2-enoic acid ethyl ester (intermediatecompound 25). e) Intermediate compound 25 (1.066 g, 0.0045 mol) wastreated under the reaction conditions described in Example A.1d.Yielding: 0.99 g (88%) of4-[2-(hydroxyimino-methyl)-pyridin-3-yloxy]-but-2-enoic acid ethyl ester(intermediate compound 26).

f) To a solution of intermediate compound 26 (0.99 g, 0.00395 mol) andpyridine (catalytic amount), N-chlorosuccinimide (0.581 g, 0.00435 mol)was added portionwise at room temperature and the reaction was heated toreflux for 30 min. Then the reaction was cooled to room temperature andtriethylamine was added (0.66 ml, 0.00474 mol). The reaction was stirredfor 2 h at room temperature, then washed with a saturated aqueoussolution of NaHCO₃. The organic layer was separated, dried (Na₂SO₄),filtered and the solvent was evaporated. Yielding: 0.98 g (100%, crudeproduct) of3a,4-dihydro-3H-2,5-dioxa-1,9-diaza-cyclopenta[a]naphthalene-3-carboxylicacid ethyl ester (intermediate compound 27).

g) Intermediate compound 27 (0.98 g, 0.0041 mol) was treated under theconditions described in Example A.1f. Yielding: 0.64 g (76%) of(3a,4-dihydro-3H-2,5-dioxa-1,9-diaza-cyclopenta[a]naphthalen-3-yl)-methanol(intermediate compound 28).

h) Intermediate compound 28 (0.64 g, 0.0031 mol) was treated under theconditions described in Example A.2 h. Yielding: 0.702 mg (80%) ofmethanesulfonic acid3a,4-dihydro-3H-2,5-dioxa-1,9-diaza-cyclopenta[a]naphthalen-3-ylmethylester (intermediate compound 29).

Example A.6

Preparation of Intermediate Compound 36

a) To a solution of 3-methoxythiophene (4.46 ml, 0.043 mol) in 60 ml ofThF, 18.92 ml (0.047 mol) of a 2.5M solution of butyllithium intetrahydrofuran were added dropwise at room temperature under nitrogenatmosphere. The reaction was heated to reflux for 2 h, then cooled to−10° C. and DMF (4.31 ml, 0.056 mol) was added dropwise. The resultingreaction mixture was stirred at room temperature overnight. Then a 10%aqueous solution of ammonium chloride was added and the mixture wasextracted with ethyl ether. The organic layer was separated, dried(Na₂SO₄), filtered and the solvent was evaporated. The residue waspurified by short open column chromatography over silica gel (eluent:DCM). The desired fractions were collected and the solvent evaporated.Yielding: 4.51 g (73%) of 3-methoxy-thiophene-2-carbaldehyde(intermediate compound 30).

b) To a solution of intermediate compound 30 (4.51 g, 0.0316 mol) in 215ml of DCM, 3.3 ml (0.0345 mol) of BBr₃ were added at 0° C. undernitrogen atmosphere. The reaction was stirred overnight at roomtemperature. The reaction was cooled to 0° C. and additional 0.52 ml(0.0055 mol) of BBr₃ were added. The reaction was stirred overnight atroom temperature, then treated with some drops of MeOH and with asaturated aqueous solution of ammonium chloride. The mixture wasfiltrated through CELITE and the filtrate organic layer was separated,dried (Na₂SO₄), filtered and the solvent was evaporated. The residue waspurified by short open column chromatography over silica gel (eluent:DCM/Ethyl acetate 96/4). The desired fractions were collected and thesolvent evaporated. Yielding: 2.91 g (71%) of3-hydroxy-thiophene-2-carbaldehyde (intermediate compound 31).

c) Intermediate compound 31 (2.92 g, 0.0219 mol) was treated under theconditions described in Example A.1c. Yielding: 5,74 g (95%) of4-(2-formyl-thiophen-3-yloxy)-but-2-enoic acid ethyl ester (intermediatecompound 32).

d) Intermediate compound 32 (4.87 g, 0.0197 mol) was treated under theconditions described in Example A.1d. Yielding: 5.78 g (100%, crudeproduct) of 4-[2-(hydroxyimino-methyl)-thiophen-3-yloxy]-but-2-enoicacid ethyl ester (intermediate compound 33).

e) Intermediate compound 33 (5.03 g, 0.0194 mol) was treated under theconditions described in Example A.1e. Yielding: 1.61 g (27%) of3a,4-dihydro-3H-2,5-dioxa-8-thia-1-aza-as-indacene-3-carboxylic acidethyl ester (intermediate compound 34).

f) Intermediate compound 34 (1.4 g, 0.0055 mol) was treated under theconditions described in Example A.1f. Yielding: 1.02 g (87%) of(3a,4-dihydro-3H-2,5-dioxa-8-thia-1-aza-as-indacen-3-yl)-methanol(intermediate compound 35).

g) Intermediate compound 35 (1.17 g, 0.0055 mol) was treated under theconditions described in Example A.2 h. Yielding: 1.56 g (97%) ofmethanesulfonic acid3a,4-dihydro-3H-2,5-dioxa-8-thia-1-aza-as-indacen-3-ylmethyl ester(intermediate compound 36).

B. Preparation of the Final Compounds

Example B.1

Preparation of Final Compound 1

A mixture of intermediate compound 7 (prepared according to example A.1)(2.12 g, 0.0066 mol) (E) 1-(2-methyl-3-phenyl-2-propenyl)piperazine(2.16 g, 0.010 mol) KI (1.1 g, 0.0066 mol) and K₂CO₃ (0.91 g, 0.0066mol) in methylisobutylketone (50 ml) was stirred and refluxed overnight.Then water was added and the mixture was extracted with DCM. The organicsolution was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue was purified by short open column chromatographyover silica gel (eluent: DCM/2-propanone 4/1 and 1/1). The desiredfractions were collected and the solvent evaporated. The residue waswashed with diisopropylether and the solid was collected. Yielding: 2.3g (79%) of3-[4-(2-Methyl-3-phenyl-allyl)-piperazin-1-ylmethyl]-3a,4-dihydro-3H-2,5-dioxa-1,7-diaza-dicyclopenta[a,g]naphthalene(final compound 1).

Example B.2

Preparation of Final Compound 7

To a mixture of compound 1 (100 mg, 0.23 mmol), Na₂CO₃ (30 mg, 0.28mmol), KOH powered (16 mg, 0.28 mmol) in 2 ml of acetonitrile and 2 mlof THF; methyliodide (17.4 μl, 0.28 mmol) was added portionwise at 0° C.The reaction was stirred at room temperature overnight. Then a 10%aqueous solution of ammonium chloride was added and the mixture wasextracted with DCM. The organic solution was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue was purified byshort open column chromatography over silica gel (eluent: DCM/MeOH98/2). The desired fractions were collected and the solvent evaporated.The residue was washed with diisopropylether and the solid wascollected. Yielding: 51.2 mg (49%) of7-methyl-3-[4-(2-methyl-3-phenyl-allyl)-piperazin-1-ylmethyl]-3a,4-dihydro-3H,7H-2,5-dioxa-1,7-diaza-dicyclopenta[a,g]naphthlene(final compound 7).

Example B.3

Preparation of Final Compound 10

Final compound 1 (100 mg, 0.23 mmol) was treated with methylbromoacetate (26.5 μl, 0.28 mmol) under the conditions described inExample B.2. Yielding: 39.0 mg (33%) of{3-[4-(2-methyl-3-phenyl-allyl)-piperazin-1-ylmethyl]-3a,4-dihydro-3H-2,5-dioxa-1,7-diaza-dicyclopenta[a,g]naphthlen-7-yl}-acetic acid methyl ester(final compound 10).

Example B.4

Preparation of Final Compound 8

To a solution of final compound 10 (0.24 g, 4.5 mmol) in 5 ml oftetrahydrofuran and 1 ml of MeOH, sodium borohydride (42.7 mg, 1.13mmol) was added portionwise at 0° C. The reaction was stirred for 2 h atroom temperature. Then a 10% aqueous solution of ammonium chloride wasadded and the mixture was extracted with DCM. The organic solution wasseparated, dried (MgSO4), filtered and the solvent was evaporated. Theresidue was purified by short open column chromatography over silica gel(eluent: DCM/MeOH 98/2 and 95/5). The desired fractions were collectedand the solvent evaporated. The residue was washed with diisopropyletherand the solid was collected. Yielding: 87 mg (40%) of2-{3-[4-(2-methyl-3-phenyl-allyl)-piperazin-1-ylmethyl]-3a,4-dihydro-3H-2,5-dioxa-1,7-diaza-dicyclopenta[a,g]naphthalen7-ylethanol(final compound 8).

Example B.5

Preparation of Final Compound 11

To a mixture of final compound 1 (100 mg, 0.23 mmol) and polymersupported BEMP(2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diaza-phosphorine,loading 2.2 mmol/g) (0.26 g, 0.58 mmol) in 2 ml of DCM, acetyl chloride(40 μl, 0.56 mmol) was added. The reaction was stirred for 1 h at roomtemperature. Then the solid was filtered of through a CELITE pad and thefiltrate solvent was evaporated. The residue was purified by short opencolumn chromatography over silica gel (eluent: DCM/2-propanone 4/1). Thedesired fractions were collected and the solvent evaporated. The residuewas washed with diisopropylether and the solid was collected. Yielding:58.4 mg (52%) of1-{3-[4-(2-methyl-3-phenyl-allyl)-piperazin-1-ylmethyl]-3a,4-dihydro-3H-2,5-dioxa-1,7-diaza-dicyclopenta[a,g]naphthalen7-yl}-ethanone(final compound 11).

Example B.6

Preparation of Final Compounds 16 and 17

Final compound 8 (prepared according to B.4) (0.8 g, 0.00164 mol) waspurified by high-performance liquid chromatography over Chiralcel OJ(eluent: hexane/MeOH/EtOH 20/24/56). The desired fractions werecollected and the solvent was evaporated. Yield: fractions A and B.

-   Fraction A: 256 mg (32%) of    A-2-{3-[4-(2-methyl-3-phenyl-allyl)-piperazin-1-ylmethyl]-3a,4-dihydro-3H-2,5-dioxa-1,7-diaza-dicyclopenta[a,g]naphthalen7-yl}-ethanol    (final compound 16).-   Fraction B: 276 mg (35%) of    B-2-{3-[4-(2-methyl-3-phenyl-allyl)-piperazin-1-ylmethyl]-3a,4-dihydro-3H-2,5-dioxa-1,7-diaza-dicyclopenta[a,g]naphthalen7-yl}-ethanol    (final compound 17).

Example B.7

Preparation of Final Compound 18

A mixture of intermediate compound 16 (prepared according to exampleA.3) (015 g, 0.56 mmol) and (E)1-(2-methyl-3-phenyl-2-propenyl)piperazine (0.242 g, 1.12 mmol) in 1 mlof 1,4-dioxane was heated at 100° C. for 1 h. The mixture was taken upin DCM and washed with water. The organic solution was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue waspurified by short open column chromatography over silica gel (eluent:DCM/Ethyl acetate 1/1, 1/2 and pure Ethyl acetate). The desiredfractions were collected and the solvent evaporated. The residue wasconverted into its etanodioic acid salt in EtOH and the solid wascollected. Yielding: 76 mg (27%) of3-[4-(2-methyl-3-phenyl-allyl)-piperazin-1-ylmethyl]-3a,4-dihydro-3H-2,5-dioxa-1,7-diaza-cyclopenta[a]naphthaleneoxalate salt (1/1) (final compound 18).

Example B.8

Preparation of Final Compound 19

Intermediate compound 15 (prepared according to example A.2) (72 mg,0.253 mmol) was treated with 1-Naphthalen-2-ylmethyl-piperazine (63 mg,0.278 mmol) under the conditions described in Example B.1. The productwas converted into its ethanodioic acid salt in EtOH. The solvent wasevaporated and the residue was washed with acetonitrile/diisopropylether. The solid was collected. Yielding: 11 mg (8%) of3-(4-naphthalen-2-ylmethyl-piperazin-1-ylmethyl)-3a,4-dihydro-3H-2,5-dioxa-1,7-diaza-cyclopenta[a]naphthaleneoxalate salt (1/1) (final compound 19).

Example B.9

Preparation of Final Compound 22

Intermediate compound 21 (prepared according to example A.4) (120 mg,0.446 mmol) and (E) 1-(2-methyl-3-phenyl-2-propenyl)piperazine (192 mg,0.892 mmol) in 1 ml of 1,4-dioxane was treated under the conditionsdescribed in Example B.7. Yielding: 34 mg (15%) of3-[4-(2-methyl-3-phenyl-allyl)-piperazin-1-ylmethyl]-3a,4-dihydro-3H-2,5-dioxa-1,6-diaza-cyclopenta[a]naphthaleneoxalate salt (final compound 22).

Example B.10

Preparation of Final Compound 24

A mixture of intermediate compound 29 (prepared according to exampleA.5) (200 mg, 0.703 mmol),1-[3-(4-Fluoro-phenyl)-2-methyl-allyl]-piperazine (198 mg, 0.844 mmol)and K₂CO₃ (117 g, 0.844 mmol) in methylisobutylketone (5 ml) was stirredand refluxed overnight. Then water was added and the mixture wasextracted with DCM. The organic solution was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue was purified byshort open column chromatography over silica gel (eluent: Heptane/Ethylacetate 3/7, 2/8 and Ethyl acetate). The desired fractions werecollected and the solvent evaporated. The residue was washed withacetonitrile/diisopropylether and the solid was collected. Yielding: 89mg (30%) of3-{4-[3-(4-fluoro-phenyl)-2-methyl-allyl]-piperazin-1-ylmethyl}-3a,4-dihydro-3H-2,5-dioxa-1,9-diaza-cyclopenta[a]naphthalene(final compound 24).

Example B.11

Preparation of Final Compound 27

Intermediate compound 36 (prepared according to example A.6) (0.5 g,0.0017 mol) and 1-[3-(4-Fluoro-phenyl)-2-methyl-allyl]-piperazine (0.81g, 0.0034 mol) were treated under the conditions described in ExampleB.1. Yielding: 0.15 g (20%) of3-{4-[3-(4-fluoro-pheny)-2-methyl-allyl]-piperazin-1-ylmethyl}-3a,4-dihydro-3H-2,5-dioxa-8-thia-1-aza-as-indacene(final compound 27).

The following final compounds were made accordingly:

TABLE 1

Co.No. ExpNo.

—R¹

Phys.data  1 B.1

—H

[3α(E),3aα]  2 B.1

—H

[3α(E),3aα]  3 B.1

—H

[3α(E),3aα]  4 B.1

—H

[3α,3aα]  5 B.1

—H

[3α,3aα]  6 B.1

—H

[3α(E),3aα]  7 B.2

—CH₃

[3α(E),3aα]  8 B.4

[3α(E),3aα]  9 B.2

[3α(E),3aα] 10 B.3

[3α(E),3aα] 11 B.5

[3α(E),3aα] 12 B.5

[3α(E),3aα] 13 B.5

[3α(E),3aα] 14 B.5

[3α(E),3aα] 15 B.2

[3α(E),3aα] 16 B.6

A-[3α(E),3aα] 17 B.6

B-[3α(E),3aα] 18 B.7

—

[3α(E),3aα]C₂H₂O₄(1:1) 19 B.8

—

[3α,3aα]C₂H₂O₄(1:1) 20 B.8

—

[3α(E),3aα] 21 B.7

—

[3α(E),3aα]C₂H₂O₄(1:1) 22 B.9

—

[3α(E),3aα]C₂H₂O₄(1:1) 23  B.10

—

[3α(E),3aα]C₂H₂O₄(1:2) 24  B.10

—

[3α(E),3aα] 25  B.10

—

[3α(E),3aα] 26  B.10

—

[3α,3aα] 27  B.11

—

[3α(E),3aα]

For a selection of compounds, melting points were obtained with a Büchimelting point apparatus B-545. The heating medium is a metal block. Themelting of the sample is visually observed by a magnifying lense and abig light contrast. Melting points are measured with a temperaturegradient of 3 degrees Celsius/minute. The results are summarized inTable 1b.

TABLE 1b Melting points Melting point Co. No. (° C.) Visual observation1 173.2-179.1 At 173.2° C. shrink, at 177.1° C. red foam crystals, at179.1° C. red liquid 2 169.8-184.3 At 169.8° C. shrink, at 181.5° C. redfoam crystals, at 184.3 red liquid 3 158.9-170.1 At 158.9° C. shrink, at170.1° C. red brown liquid 4 176.6-207.3 At 176.6° C. shrink, at 207.3°C. red sticky product 5 131.1-154.6 At 131.1° C. shrink, at 154.6° C.brown liquid 6 91.6-99.2 At 91.6° C. shrink, at 99.2° C. colourlessliquid and orange sticky 12 107.5-114.2 At 107.5° C. shrink, at 114.2°C. yellow liquid 16 167.9-170.2 At 167.9° C. shrink, at 170.2° C. lightyellow liquid 17 167.5-170.5 At 167.5° C. shrink, at 170.5° C. yellowliquid 18 216.8-220.5 At 216.8° C. shrink, at 218.4° C. black foamcrystals, at 220.5° C. black liquid 20 128.1-136.8 At 128.1° C. shrink,at 136.8° C. light yellow liquid 24 145.6-152.3 At 145.6° C. shrink, at152.3° C. black liquid 25 128.1-131.1 At 128.1° C. shrink, at 131.1° C.light yellow liquid 26 152.4-158.1 At 152.4° C. shrink, at 158.4° C.light yellow liquid 27 142.3-146.0 At 142.3° C. shrink, at 146.0° C.colourless liquidC. Pharmacological Examples

Example C1

Binding Experiment for α₂-adrenergic Receptor Subtypes and for 5-HTTransporter

General

The interaction of the compounds of Formula (I) with hα₂-receptors andh5-HT-transporters was assessed in in vitro radioligand bindingexperiments. In general, a low concentration of a radioligand with ahigh binding affinity for a particular receptor or transporter isincubated with a sample of a tissue preparation enriched in a particularreceptor or transporter or with a preparation of cells expressing clonedhuman receptors in a buffered medium. During the incubation, theradioligand binds to the receptor or transporter. When equilibrium ofbinding is reached, the receptor bound radioactivity is separated fromthe non-bound radioactivity, and the receptor- or transporter-boundactivity is counted. The interaction of the test compounds with thereceptor is assessed in competition binding experiments. Variousconcentrations of the test compound are added to the incubation mixturecontaining the receptor- or transporter preparation and the radioligand.The test compound in proportion to its binding affinity and itsconcentration inhibits binding of the radioligand. The radioligand usedfor hα_(2A), hα_(2B) and hα_(2C) receptor binding was [³H]-raulwolscineand for the h5-HT transporter was [³H]paroxetine.

Cell Culture and Membrane Preparation.

CHO cells, stabile transfected with human adrenergic-α_(2A)-, -α_(2B) orα_(2C) receptor cDNA, were cultured in Dulbecco's Modified Eagle'sMedium (DMEM)/Nutrient mixture Ham's F12 (ratio 1:1)(Gibco,Gent-Belgium) supplemented with 10% heat inactivated fetal calf serum(Life Technologies, Merelbeke-Belgium) and antibiotics (100 IU/mlpenicillin G, 100 μg/ml streptomycin sulphate, 110 μg/ml pyruvic acidand 100 μg/ml L-glutamine). One day before collection, cells wereinduced with 5 mM sodiumbutyrate. Upon 80-90% of confluence, cells werescraped in phosphate buffered saline without Ca²⁺ and Mg²⁺ and collectedby centrifugation at 1500×g for 10 min. The cells were homogenised inTris-HCl 50 mM using an Ultraturrax homogenizer and centrifuged for 10min at 23,500×g. The pellet was washed once by resuspension andrehomogenization and the final pellet was resuspended in Tris-HCl,divided in 1 ml aliquots and stored at −70° C.

Binding Experiment for α₂-adrenergic Receptor Subtypes

Membranes were thawed and re-homogenized in incubation buffer(glycylglycine 25 mM, pH 8.0). In a total volume of 500 μl, 2-10 μgprotein was incubated with [³H]raulwolscine (NET-722) (New EnglandNuclear, USA) (1 nM final concentration) with or without competitor for60 min at 25° C. followed by rapid filtration over GF/B filter using aFiltermate196 harvester (Packard, Meriden, Conn.). Filters were rinsedextensively with ice-cold rinsing buffer (Tris-HCl 50 mM pH 7.4).Filter-bound radioactivity was determined by scintillation counting in aTopcount (Packard, Meriden, Conn.) and results were expressed as countsper minute (cpm). Non-specific binding was determined in the presence of1 μM oxymetazoline for hα_(2A)- and hα_(2B) receptors and 1 μMspiroxatrine for hα_(2C) receptors.

Binding Experiment for 5-HT Transporter

Human platelet membranes (Oceanix Biosciences Corporation, Hanover, Md.,USA) were thawed, diluted in buffer (Tris-HCl 50 mM, 120 mM NaCl and 5mM KCl) and quickly (max 3 s) homogenised with an Ultraturraxhomogenizer. In a total volume of 250 μL, 50-100 μg protein wasincubated with [³H]paroxetine (NET-869) (New England Nuclear, USA) (0.5nM final concentration) with or without competitor for 60 min at 25 ° C.Incubation was stopped by rapid filtration of the incubation mixtureover GF/B filters, pre-wetted with 0.1% polyethyleneamine, using aFiltermate196 harvester (Packard, Meriden, Conn.). Filters were rinsedextensively with ice-cold buffer and radioactivity on the filters wascounted in a Topcount liquid scintillation counter (Packard, Meriden,Conn.). Data were expressed as cpm. Imipramine (at 1 μM finalconcentration) was used to determine the non-specific binding.

Data Analysis and Results

Data from assays in the presence of compound were calculated as apercentage of total binding measured in the absence of test compound.Inhibition curves, plotting percent of total binding versus the logvalue of the concentration of the test compound, were automaticallygenerated, and sigmoidal inhibition curves were fitted using non-linearregression. The pIC₅₀ values of test compounds were derived fromindividual curves.

All compounds according to Formula (I) produced an inhibition at leastat the hα_(2A) site (but often also at the hα_(2B) and hα_(2C) sites)and simultaneously at the 5-HT transporter site of more than 50% (pIC₅₀)at a test concentration ranging between 10⁻⁶ M and 10⁻⁹ M in aconcentration-dependent manner.

TABLE 2 Pharmacological data. Co. No hα_(2A) hα_(2B) hα_(2C) 5-HTT 209.2 — 8.8 7.6 18 8.9 — 8.8 6.7 23 8.9 — 8.4 6.7 18 8.8 8.8 8.8 7.5 278.7 — 8.1 7.1 25 8.7 — 7.8 6.2 11 8.6 — 9.0 8.2 14 8.5 — 8.9 8.4 7 8.5 —9.1 8.3 13 8.4 — 8.4 7.9 1 8.3 8.4 9.0 8.4 24 8.2 — 7.5 6.7 21 8.2 — 7.87.1 12 8.2 — 8.5 7.7 26 8.1 — 7.3 7.4 6 8.1 — 8.6 8.3 2 8.1 8.3 9.0 8.39 8.1 8.1 9.1 8.7 19 8.0 — 7.4 7.0 17 8.0 8.3 8.7 6.3 10 7.9 8.3 9.1 8.715 7.9 8.4 8.6 8.3 3 7.8 7.6 8.7 8.2 8 7.8 8.3 8.7 8.4 4 7.6 7.3 8.4 8.85 6.7 — 7.4 7.8 16 6.5 7.7 7.3 6.3 22 6.2 — 7.1 5.2

1. A compound according to the general Formula (I)

the pharmaceutically acceptable acid or base addition salts thereof, thestereochemically isomeric forms thereof, or the N-oxide forms thereof,wherein: X is CH₂, N—R⁷, S or O; R⁷ is selected from the groupconsisting of hydrogen, alkyl, Ar, Ar-alkyl, alkylcarbonyl,alkyloxycarbonyl and mono- and dialkylaminocarbonyl; B is a radical,optionally substituted with r radicals R′, according to anyone ofFormula (B-a) or (B-b) and fused to the isoxazolinyl moiety by either ofthe bond pairs (c,d), (d,e) or (e,f)

wherein Het is an optionally substituted 5- or 6-membered heterocyclicring, selected from the group consisting of pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxadiazolyland triazolyl; each R¹ is, independently from each other, selected fromthe group consisting of hydrogen, hydroxy, amino, nitro, cyano, halo andalkyl and, only when R′ is attached to a N-atom, is further selectedfrom the group of alkyloxyalkyl, alkyloxyalkyloxyalkyl,alkyloxycarbonylalkyl, fonnyl, alkylcarbonyl, alkyloxycarbonyl,alkyloxyalkylcarbonyl and mono- and dialkylaminocarbonyl; r is aninteger ranging from 0 to 6; a and b are asymmetric centers; (CH₂)_(m)is a straight hydrocarbon chain of m carbon atoms, m being an integerranging from 1 to 4; Pir is a radical according to any one of Formula(IIa), (IIb) or (IIc)

optionally substituted with n radicals R⁸, wherein: each R⁸ isindependently from each other, selected from the group consisting ofhydroxy, amino, nitro, cyano, halo and alkyl; n is an integer rangingfrom 0 to 5; R⁹ is selected from the group consisting of hydrogen, alkyland formyl; R³ represents an optionally substituted aromatic homocyclicor heterocyclic ring system together with an optionally substituted andpartially or completely hydrogenated hydrocarbon chain of 1 to 6 atomslong with which said ring system is attached to the Pir radical and ofwhich may contain one or more heteroatoms selected from the group of O,N and S; Ar is phenyl or naphthyl, optionally substituted with one ormore halo, cyano, oxo, hydroxy, alkyl, formyl, alkyloxy or aminoradicals; and alkyl represents a straight or branched saturatedhydrocarbon radical having from 1 to 6 carbon atoms or a cyclicsaturated hydrocarbon radical having from 3 to 6 carbon atoms,optionally substituted with one or more halo, cyano, oxo, hydroxy,formyl or amino radicals.
 2. The compound according to claim 1, whereinR³ is a radical according to any one of Formula (IIIa), (IIIb) or (IIIc)

wherein: d is a single bond while Z is a bivalent radical selected fromthe group consisting of —CH₂—, —C(═O)—, —CH(OH)—, —C(═N—OH)—,—CH(alkyl)—, —O—, —S—, —S(═O)—, —NH— and —SH—; or d is a double bondwhile Z is a trivalent radical of formula ═CH— or ═C(alkyl)—; A is a 5-or 6-membered aromatic homocyclic or heterocyclic ring, selected fromthe group consisting of phenyl, pyranyl, pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, thienyl, isothiazolyl, pyrrolyl, imidazolyl,pyrazolyl, furanyl, oxadiazolyl and isoxazolyl; P is an integer rangingfrom 0 to 6; R⁴ and R⁵ are each, independently from each other, selectedfrom the group consisting of hydrogen, alkyl, Ar, biphenyl, halo andcyano ; or R⁴ and R⁵ may be taken together to form a bivalent radical—R⁴—R⁵— selected from the group consisting of —CH₂—, ═CH—, —CH₂—CH₂—,—CH═CH—, —O—, —NH—, ═N—, —S—, —CH₂N(-alkyl)—, —N(-alkyl)CH₂—, —CH₂NH—,—NHCH₂—, —CH═N—, —N═CH—, —CH₂O— and —OCH₂—; each R⁶ is independentlyfrom each other, selected from the group consisting of hydroxy, amino,nitro, cyano, halo, carboxyl, alkyl, Ar, alkyloxy, Ar-oxy,alkylcarbonyloxy, alkyloxycarbonyl, alkylthio, mono- and di(alkyl)amino,alkylcarbonylamino, mono- and di(alkyl)aminocarbonyl, mono- anddi(alkyl)aminocarbonyloxy, mono- and di(alkyl)aminoalkyloxy; or twovicinal radicals R⁶ may be taken together to form a bivalent radical—R⁶—R⁶— selected from the group consisting of —CH₂—CH₂—O—, —O—CH₂—CH₂—,—O—CH₂—C(═O)—, —C(═O)—CH₂—O—, —O—CH₂—O—, —CH₂—O—CH₂—, —O—CH₂—CH₂—O—,—CH═CH—CH═CH—, —CH═CH—CH═N—, —CH═CH—N═CH—, —CH═N—CH═CH—, —N═CH—CH═CH—,—CH₂—CH₂—CH₂—, —CH₂—CH₂—C(═O)—, —C(═O)—CH₂—CH₂—, —CH₂—C(═O)—CH₂— and—CH₂—CH₂—CH₂—CH₂ and R¹⁶ is selected from the group consisting ofhydrogen, alkyl, Ar and Ar-alkyl.
 3. A compound according to claim 2,wherein X=O; m=1; B is a radical according to Formula (B-a) or (B-b),Pir is a radical according to Formula (IIa) wherein n=0 ; R³is a radicalaccording to according to any one of Formula (IIIa), (IIIb) or (IIIc)wherein d is a double bond while Z is a trivalent radical of formula═CH— or ═C(alkyl)—; A is a phenyl ring; R⁴is hydrogen or alkyl ; R⁵ andR¹⁶ are hydrogen; R⁶is hydrogen or halo and p=1.
 4. A compound accordingto claim 1, wherein Het is selected from the group consisting ofpyridinyl, thienyl and pyrrolyl, each radical optionally substituted ona N atom with a radical selected from the group consisting of hydrogen,alkyl, hydroxyalkyl, alkyloxyalkyloxyalkyl, alkyloxycarbonylalkyl,alkylcarbonyl, alkyloxycarbonyl and alkyloxyalkylcarbonyl.
 5. A methodof treating a warm-blooded animal suffering from depression, anxiety,movement disorders, psychosis, Parkinson's disease, or body weightdisorders comprising administering a compound according to claim 1 tosaid animal.
 6. A pharmaceutical composition comprising apharmaceutically acceptable carrier and, as active ingredient, atherapeutically effective amount of a compound according to claim
 1. 7.A process for making a pharmaceutical composition comprising mixing acompound according to claim 1 and a pharmaceutically acceptable carrier.